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RANDY SCHEKMAN Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, USA
GENES AND PROTEINS THAT CONTROL THE SECRETORY PATHWAY Nobel Lecture, 7 December 2013 by RANDY SCHEKMAN Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, USA. Introduction George Palade shared the 1974 Nobel Prize with Albert Claude and Christian de Duve for their pioneering work in the characterization of organelles interrelated by the process of secretion in mammalian cells and tissues. These three scholars established the modern field of cell biology and the tools of cell fractionation and thin section transmission electron microscopy. It was Palade’s genius in particular that revealed the organization of the secretory pathway. He discovered the ribosome and showed that it was poised on the surface of the endoplasmic reticulum (ER) where it engaged in the vectorial translocation of newly synthesized secretory polypeptides (1). And in a most elegant and technically challenging investigation, his group employed radioactive amino acids in a pulse-chase regimen to show by autoradiograpic exposure of thin sections on a photographic emulsion that secretory proteins progress in sequence from the ER through the Golgi apparatus into secretory granules, which then discharge their cargo by membrane fusion at the cell surface (1). He documented the role of vesicles as carriers of cargo between compartments and he formulated the hypothesis that membranes template their own production rather than form by a process of de novo biogenesis (1). As a university student I was ignorant of the important developments in cell biology; however, I learned of Palade’s work during my first year of graduate school in the Stanford biochemistry department. -
ER-To-Golgi Trafficking and Its Implication in Neurological Diseases
cells Review ER-to-Golgi Trafficking and Its Implication in Neurological Diseases 1,2, 1,2 1,2, Bo Wang y, Katherine R. Stanford and Mondira Kundu * 1 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; [email protected] (B.W.); [email protected] (K.R.S.) 2 Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA * Correspondence: [email protected]; Tel.: +1-901-595-6048 Present address: School of Life Sciences, Xiamen University, Xiamen 361102, China. y Received: 21 November 2019; Accepted: 7 February 2020; Published: 11 February 2020 Abstract: Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. Keywords: COPII trafficking; endoplasmic reticulum; Golgi apparatus; neurological disease 1. Overview Approximately one-third of all proteins encoded by the mammalian genome are exported from the endoplasmic reticulum (ER) and transported to the Golgi apparatus, where they are sorted for delivery to their final destination in membrane compartments or secretory vesicles [1]. -
Neurosecretory Vesicles Can Be Hybrids of Synaptic Vesicles
Proc. Natl. Acad. Sci. USA Vol. 92, pp. 7342-7346, August 1995 Neurobiology Neurosecretory vesicles can be hybrids of synaptic vesicles and secretory granules (small dense core vesicles/sympathetic neurons) RUDOLF BAUERFEIND, RuTH JELINEK, ANDREA HELLWIG, AND WIELAND B. HUrTNER* Institute for Neurobiology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany Communicated by Philip Siekevitz, The Rockefeller University, New York, NY, March 27, 1995 ABSTRACT We have investigated the relationship of the This implies that only the regulated, but not the constitutive, so-called small dense core vesicle (SDCV), the major cate- pathway of protein secretion contributes to the biogenesis of cholamine-containing neurosecretory vesicle of sympathetic SDCVs. This concept has been extended to the biogenesis of neurons, to synaptic vesicles containing classic neurotrans- synaptic vesicles in general (4, 9, 10) but has not provided a mitters and secretory granules containing neuropeptides. satisfactory explanation for the very low abundance, in secre- SDCVs contain membrane proteins characteristic of synaptic tory granules, of certain membrane proteins that are major vesicles such as synaptophysin and synaptoporin. However, components of classic synaptic vesicles. The other concept, SDCVs also contain membrane proteins characteristic of which originated from the demonstration that the classic certain secretory granules like the vesicular monoamine synaptic vesicle membrane is distinct from that ofthe secretory transporter and the membrane-bound form of dopamine granule, has viewed the SDCVs, which lack secretory proteins f3-hydroxylase. In neurites of sympathetic neurons, synapto- and morphologically resemble classic synaptic vesicles, as physin and dopamine 8-hydroxylase are found in distinct synaptic vesicles that simply contain vesicular amine transport- vesicles, consistent with their transport from the trans-Golgi ers instead of uptake systems for classic neurotransmitters (1, network to the site of SDCV formation in constitutive secre- 8). -
Immunofluorescence Investigations on Neuroendocrine Secretory Protein 55 (NESP55) in Nervous Tissues
Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden Immunofluorescence Investigations on Neuroendocrine Secretory Protein 55 (NESP55) in Nervous Tissues Yongling Li 李永灵 Göteborg 2008 1 Cover picture Confocal images showing the intracellular distribution of NESP55-IR (green), as compared to TGN38-IR (red), in preganglionic sympathetic neurons (top panel) and spinal motoneurons (lower panel) in the rat. Printed in Sweden by Geson, Göteborg 2008 ISBN 978-91-628-7489-6 2 CONTENTS ABSTRACT ...................................................................................................................5 ABBREVIATION...........................................................................................................6 LIST OF PAPERS ..........................................................................................................7 INTRODUCTION ..........................................................................................................9 Chromogranins..........................................................................................................9 Chromogranin family members ...............................................................................9 Structural properties ..............................................................................................10 Tissue distribution and subcellular localization...................................................... 10 Intracellular and extracellular functions ................................................................ -
Secretory Protein Traffic. Chromogranin a Contains a Dominant Targeting Signal for the Regulated Pathway
Secretory protein traffic. Chromogranin A contains a dominant targeting signal for the regulated pathway. R J Parmer, … , L J Helman, L N Petz J Clin Invest. 1993;92(2):1042-1054. https://doi.org/10.1172/JCI116609. Research Article Secretory proteins are targeted into either constitutive (secreted upon synthesis) or regulated (stored in vesicles and released in response to a secretagogue) pathways. To investigate mechanisms of protein targeting into catecholamine storage vesicles (CSV), we stably expressed human chromogranin A (CgA), the major soluble protein in human CSV, in the rat pheochromocytoma PC-12 cell line. Chromaffin cell secretagogues (0.1 mM nicotinic cholinergic agonist, 55 mM K+, or 2 mM Ba++) caused cosecretion of human CgA and catecholamines from human CgA-expressing cells. Sucrose gradients colocalized human CgA and catecholamines to subcellular particles of the same buoyant density. Chimeric proteins, in which human CgA (either full-length [457 amino acids] or truncated [amino-terminal 226 amino acids]) was fused in-frame to the ordinarily nonsecreted protein chloramphenicol acetyltransferase (CAT), were expressed transiently in PC-12 cells. Both constructs directed CAT activity into regulated secretory vesicles, as judged by secretagogue- stimulated release. These data demonstrate that human CgA expressed in PC-12 cells is targeted to regulated secretory vesicles. In addition, human CgA can divert an ordinarily non-secreted protein into the regulated secretory pathway, consistent with the operation of a dominant targeting signal for the regulated pathway within the peptide sequence of CgA. Find the latest version: https://jci.me/116609/pdf Secretory Protein Traffic Chromogranin A Contains a Dominant Targeting Signal for the Regulated Pathway Robert J. -
Protein Secretion: Puzzling Receptors Christoph Thiele, Hans-Hermann Gerdes and Wieland B
R496 Dispatch Protein secretion: Puzzling receptors Christoph Thiele, Hans-Hermann Gerdes and Wieland B. Huttner All known sorting receptors for soluble cargo in the sorting at these two levels appears to vary between cell secretory pathway are transmembrane proteins. For types. In the most abundant cell type endowed with regu- sorting to the regulated pathway, however, a lated protein secretion, the neuron, membrane traffic to subpopulation of secretory proteins, associated with the either the somatodendritic or the axonal cell surface membrane but not membrane-spanning, appears to link diverges in the trans-Golgi network [7], which is confined cargo and membrane in storage granule biogenesis. to the neuronal cell body. In neurons, therefore, the trans- Golgi network is likely to be a major site of protein sorting Address: Department of Neurobiology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany. during the biogenesis of neuropeptide-containing secre- tory granules, which typically are targeted to the axon, and Current Biology 1997, 7:R496–R500 vesicles targeted to the dendrites. (Some protein sorting may continue as neuronal secretory granules undergo mat- http://biomednet.com/elecref/09609822007R0496 uration during axonal transport.) © Current Biology Ltd ISSN 0960-9822 In exocrine cells, the rate of vesicle traffic to the basolat- Secretory granules are specialized organelles that mediate eral surface for cell maintenance, relative to that of apical regulated protein secretion — the exocytotic release of secretory granules to fulfill the specialized function of the proteins in response to a stimulus. They contain a selected cell, is presumably much less than in a peptidergic neuron set of the soluble and membrane-bound proteins that, fol- with an extensive dendritic tree, such as a cerebellar Purk- lowing synthesis in the rough endoplasmic reticulum, are inje cell. -
Review the Sorting and Trafficking of Lysosomal Proteins
Histol Histopathol (2006) 21: 899-913 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review The sorting and trafficking of lysosomal proteins X. Ni, M. Canuel and C.R. Morales Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada Summary. For a long time lysosomes were considered phosphate, to allow its recognition by a sorting receptor. terminal organelles involved in the degradation of Protein sorting in most eukaryotic cells may also involve different substrates. However, this view is rapidly protein-protein interactions between the cargo and the changing by evidence demonstrating that these receptor. Consequently, eukaryotic cells may have an organelles and their content display specialized functions additional repertoire of receptors that recognize amino in addition to the degradation of substances. Many acid sequences and/or motifs in the lysosomal cargo. lysosomal proteins have been implicated in specialized Such motifs have the property to specify the sorting and cellular functions and disorders such as antigen final destination of the cargo. This possibility is processing, targeting of surfactant proteins, and most discussed in the present review. lysosomal storage disorders. To date, about fifty To exit a sorting compartment a receptor must lysosomal hydrolases have been identified, and the interact with cytoplasmic coat proteins such as adaptor majority of them are targeted to the lysosomes via the proteins, ARF and clathrin, that cause vesicles to bud mannose-6-phosphate receptor (M6P-Rc). However, from donor membranes (trans-Golgi network/TGN) and recent studies on the intracellular trafficking of the non- to traffic to acceptor membranes (late endosomes and enzymic lysosomal proteins prosaposin and GM2 lysosomes). -
Membrane Trafficking and Vesicle Fusion Post-Palade Eraresearchers Winthenobel Prize
GENERAL ARTICLE Membrane Trafficking and Vesicle Fusion Post-Palade EraResearchers WintheNobel Prize Riddhi Atul Jani and Subba Rao Gangi Setty The functions of the eukaryotic cell rely on membrane- bound compartments called organelles. Each of these possesses dis- tinct membrane composition and unique function. In the 1970’s, during George Palade’s time, it was unclear how these organelles communicate with each other and perform their biological functions. The elegant research work of James E (left) Riddhi Atul Jani is a Rothman, Randy W Schekman and Thomas C Südhof identi- graduate student in Subba fied the molecular machinery required for membrane traf- Rao’s Lab at MCB, IISc. She is interested in ficking, vesicle fusion and cargo delivery. Further, they also studying the SNARE showed the importance of these processes for biological func- dynamics during melano- tion. Their novel findings helped to explain several biological some biogenesis. phenomena such as insulin secretion, neuron communication (right) Subba Rao Gangi and other cellular activities. In addition, their work provided Setty is an Assistant clues to cures for several neurological, immunological and Professor at the MCB, metabolic disorders. This research work laid the foundation IISc, Bangalore. He is interested in understand- to the field of molecular cell biology and these post-Palade ing the disease associated investigators were awarded the Nobel Prize in Physiology or protein trafficking Medicine in 2013. pathways in mammalian cells. Introduction Membrane Transport: In the eukaryotic cell, a majority of proteins are made in the cytosol. But the transmembrane and secretory proteins are synthesized in an organelle called the rough endoplasmic reticulum (ER). -
The Role of Microtubules in Secretory Protein Transport Lou Fourriere, Ana Joaquina Jimenez, Franck Perez, Gaelle Boncompain
The role of microtubules in secretory protein transport Lou Fourriere, Ana Joaquina Jimenez, Franck Perez, Gaelle Boncompain To cite this version: Lou Fourriere, Ana Joaquina Jimenez, Franck Perez, Gaelle Boncompain. The role of microtubules in secretory protein transport. Journal of Cell Science, Company of Biologists, 2020, 133 (2), pp.jcs237016. 10.1242/jcs.237016. hal-02986327 HAL Id: hal-02986327 https://hal.archives-ouvertes.fr/hal-02986327 Submitted on 10 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 The role of microtubules in secretory protein transport 2 3 Lou Fourriere#, Ana Joaquina Jimenez, Franck Perez and Gaelle Boncompain* 4 5 Dynamics of Intracellular Organization Laboratory, Institut Curie, PSL Research 6 University, CNRS UMR 144, Sorbonne Université, Paris, France 7 8 #Present address: The Department of Biochemistry and Molecular Biology and Bio21 9 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 10 3010, Australia 11 *Author for correspondence: [email protected] 12 13 14 Abstract 15 Microtubules are part of the dynamic cytoskeleton network and composed of tubulin 16 dimers. They are the main tracks used in cells to organize organelle positioning and 17 trafficking of cargos. -
Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress
Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress Aeid Igbariaa,b,c,1, Philip I. Merksamera,b,c,d,1, Ala Trusinae, Firehiwot Tilahuna,b,c, Jeffrey R. Johnsond,f, Onn Brandmanc,f,g, Nevan J. Krogand,f, Jonathan S. Weissmanc,f,g, and Feroz R. Papaa,b,c,2 aDepartment of Medicine, University of California, San Francisco, CA 94143; bDiabetes Center, University of California, San Francisco, CA 94143; cQuantitative Biosciences Institute, University of California, San Francisco, CA 94143; dGladstone Institute of Virology and Immunology, San Francisco, CA 94158; eCenter for Models of Life, Niels Bohr Institute, University of Copenhagen, DK 2100 Copenhagen, Denmark; fDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143; and gHoward Hughes Medical Institute, University of California, San Francisco, CA 94143 Edited by Randy Schekman, University of California, Berkeley, CA, and approved April 5, 2019 (received for review March 18, 2019) Diverse perturbations to endoplasmic reticulum (ER) functions com- UPR activation). We previously showed that differential, real- promise the proper folding and structural maturation of secretory time, quantitative eroGFP changes occurred dynamically upon proteins. To study secretory pathway physiology during such “ER general loss of ER protein-folding homeostasis in wild-type stress,” we employed an ER-targeted, redox-responsive, green cells and in a small, select group of yeast mutants (6). Here, fluorescent protein—eroGFP—that reports on ambient changes using high-throughput flow cytometry, we have extended this in oxidizing potential. Here we find that diverse ER stress regimes analysis to the entire yeast genome to query nearly all non- cause properly folded, ER-resident eroGFP (and other ER luminal essential and essential genes. -
Brefeldin a Affects Early Events but Does Not Affect Late Events Along The
Proc. Natl. Acad. Sci. USA Vol. 89, pp. 7242-7246, August 1992 Cell Biology Brefeldin A affects early events but does not affect late events along the exocytic pathway in pancreatic acinar cells (Golg complex/membrane trafflcking/exocytosis) LINDA C. HENDRICKS*t, SUSAN L. MCCLANAHAN*, GEORGE E. PALADEO, AND MARILYN GIST FARQUHARt *Division of Cellular and Molecular Medicine and tCenter for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093 Contributed by George E. Palade, April 30, 1992 ABSTRACT Brefeldin A (BFA) blocks protein export from In rat exocrine pancreatic cells we have seen yet another the endoplasmic reticulum (ER) to Golgi complex and causes variation of the effects of BFA on the compartments of the dismanting of the Golgi complex with relocation of resident exocytic pathway: Golgi cisternae disassemble to produce Golgi proteins to the ER in some cultured cells. It is not known persistent clusters ofuncoated Golgi tubules and vesicles and whether later steps in the secretory process are affected. We nonclathrin coated vesicles. Furthermore, no relocation of previously have shown that in BFA-treated rat pancreatic Golgi enzymes and antigens into the ER is detected even after lobules, there is no detectable relocation ofGolgi proteins to the prolonged BFA incubation (19). The response of the pancre- ER and, although Golgi clsternae are rapidly ntled, atic acinar cell to BFA treatment warrants further study to clusters of small smooth vesicles consisting of both bona fide determine whether this cell type represents another variant of Golgi remnants and associated vesicular carriers persist even BFA resistance and, more importantly, whether the drug with prolonged BFA exposure. -
ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart
cells Review ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart Bianca A. Meyer 1,2 and Shirin Doroudgar 1,2,* 1 Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Im Neuenheimer Feld 669, 69120 Heidelberg, Germany; [email protected] 2 DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-6221-56-34412 Received: 5 August 2020; Accepted: 3 September 2020; Published: 10 September 2020 Abstract: Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more.